A multicenter, randomized trial of prophylactic fluconazole in preterm neonates.

BACKGROUND: Invasive candida infections are a major cause of morbidity and mortality in preterm infants. We performed a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of fungal colonization and infection in very-low-birth-weight neonates. METHODS: During a 15-month period, all neonates weighing less than 1500 g at birth from eight tertiary Italian neonatal intensive care units (322 infants) were randomly assigned to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). We performed weekly surveillance cultures and systematic fungal susceptibility testing. RESULTS: Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P<0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P=0.005 for the 6-mg group and P=0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect. CONCLUSIONS: Prophylactic fluconazole reduces the incidence of colonization and invasive candida infection in neonates weighing less than 1500 g at birth. The benefit of treating candida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869 [controlled-trials.com]).

Early-onset neutropenia is a risk factor for Candida colonization in very low-birth-weight neonates.

Neutropenia is a major risk factor for bacterial colonization and sepsis in preterm neonates in the neonatal intensive care unit (NICU), but little is known about its relationships with candidal colonization (CC) in these settings. We performed a case-control study on neonates with birth weight of <1500 g admitted to our NICU during a 7-year period (1996-2003, N = 585). Through database search, infants with early-onset neutropenia (EON) (n = 68, group A) were identified and 1:1 matched with controls without EON (n = 68, group B). Microbiologic data from weekly surveillance cultures were examined to determine the presence and intensity of CC. Groups A and B were similar clinically and demographically. All group A neonates recovered from EON before the 8th day of life. Incidence of CC in the 1st month of life (at least 1 site) was significantly higher in group A (61.8% versus 35.3%, P = 0.002) and was not modified by treatment with recombinant granulocyte colony-stimulating factor. The same was true of CC intensity, expressed as the number of sites affected (P = 0.002). Incidence of candidal sepsis, mortality rates, and relative frequencies of the various subspecies of Candida among the isolates did not significantly differ between the 2 groups. In conclusion, EON in preterm neonates is a significant, independent risk factor for CC. Larger, prospective, adequately powered studies should verify whether increased CC related to neutropenia may translate into a similar increased occurrence of candidal sepsis in these settings.